rs55886062 — DPYD *13

DPYD*13 — A No-Function Star Allele in the High-Priority DPYD Panel

DPYD encodes dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme¹¹ rate-limiting enzyme
DPD catabolizes 80-90% of administered 5-fluorouracil into inactive metabolites, preventing toxic accumulation that metabolises fluoropyrimidine chemotherapy drugs. DPYD*13 (c.1679T>G, p.Ile560Ser) is a rare missense variant that produces an essentially non-functional enzyme — first described in patients presenting with life-threatening 5-fluorouracil toxicity. It is one of only four DPYD variants that CPIC classifies as clinically actionable²² CPIC classifies as clinically actionable
The other three are DPYD*2A/rs3918290, c.2846A>T/rs67376798, and the HapB3 haplotype tagged by rs75017182/rs56038477 and that the European Medicines Agency mandates testing for before fluoropyrimidine-based cancer treatment.

The Mechanism

The *13 variant is a thymine-to-guanine substitution at position 1679 of the DPYD coding sequence, which replaces isoleucine with serine at amino acid 560³³ isoleucine with serine at amino acid 560
I560S — a non-conservative substitution swapping a hydrophobic branched-chain residue for a small polar one, located in a highly conserved catalytic region of the DPD protein. Because DPYD sits on the minus strand of chromosome 1, the coding-strand T>G change appears as an A>C substitution at position 97,515,787 of the GRCh38 plus strand — which is how genome sequencing files report it.

Isoleucine 560 sits in one of the enzyme's structural domains required for proper protein folding and substrate binding; structural modelling predicts substantial disruption of the local hydrophobic core. Functional assays consistently place I560S at less than 25% of wild-type DPD activity, and CPIC treats *13 as a no-function allele equivalent in consequence to DPYD*2A⁴⁴ no-function allele equivalent in consequence to DPYD*2A
activity score 0, identical to *2A and strictly worse than the decreased-function c.2846A>T and HapB3 variants which score 0.5. That makes heterozygotes effectively 50% DPD-deficient and homozygotes (extraordinarily rare, roughly 1 in a million) functionally DPD-null.

The Evidence

DPYD*13 was first identified in the early 2000s through case reports of patients who developed life-threatening toxicity after receiving standard-dose 5-fluorouracil or capecitabine. Subsequent functional work and in silico modelling consistently place *13 in the same no-function category as *2A, and the 2017 CPIC guideline⁵⁵ 2017 CPIC guideline
Amstutz et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018 assigns it an activity score of 0 — identical to *2A and strictly worse than the decreased-function c.2846A>T and HapB3 variants, which score 0.5.

The landmark prospective Alpe-DPD study⁶⁶ landmark prospective Alpe-DPD study
Henricks et al. Lancet Oncol 2018, a Dutch multicentre trial that pre-genotyped 1,103 cancer patients before fluoropyrimidine exposure and applied genotype-guided dose reductions included DPYD*13 carriers alongside *2A, c.2846A>T, and HapB3 carriers. With a 50% initial dose reduction, severe toxicity in no-function variant carriers dropped from the 73-77% rate observed historically under standard dosing toward approximately 31% — essentially matching non-carrier background risk. Critically, matched-pair analyses showed no loss of overall survival or progression-free survival in dose-reduced carriers. A 2021 meta-analysis⁷⁷ 2021 meta-analysis
Sharma et al. Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. The Oncologist 2021 confirmed that carriers of DPYD no-function alleles — *2A and *13 combined — have a 25.6-fold higher risk of treatment-related death than non-carriers when given standard doses, and that pre-emptive genotype-guided dose reduction eliminates this excess mortality.

European-scale implementation data from the 2023 PhotoDPYD study of 8,054 Spanish cancer patients⁸⁸ 2023 PhotoDPYD study of 8,054 Spanish cancer patients
The largest prospective DPYD screening cohort to date, covering the four-variant panel mandated by the European Medicines Agency across a national oncology network found DPYD*13 at roughly 0.1% allele frequency in Spain, consistent with gnomAD v4 data showing ~0.085% non-Finnish European allele frequency (996 carriers among 1.18 million alleles sequenced). The variant is essentially absent in East Asian, South Asian, and Latino populations, very rare in African ancestry (~0.015%), and has only been documented in a handful of homozygous cases worldwide.

Practical Implications

If you carry one copy of DPYD*13, you have approximately 50% of normal DPD enzyme activity and are at dramatically elevated risk of severe, potentially fatal toxicity from fluoropyrimidine chemotherapy. These drugs — 5-fluorouracil (5-FU), capecitabine (Xeloda), and tegafur⁹⁹ 5-fluorouracil (5-FU), capecitabine (Xeloda), and tegafur
Backbone treatments for colorectal, breast, gastric, pancreatic, head-and-neck, and several other cancers — must be started at 50% of the standard dose, exactly as with DPYD*2A carriers. This is a CPIC Level A recommendation with the highest strength of evidence. Your oncologist should then use therapeutic drug monitoring (plasma 5-FU concentration measurements) to cautiously titrate the dose upward based on tolerability, typically reaching 65-80% of standard by the second or third cycle.

If you are homozygous for 13 or compound heterozygous with another no-function DPYD variant (*2A or a second *13 allele), fluoropyrimidines are **absolutely contraindicated*. The FDA label for fluorouracil¹⁰¹⁰ The FDA label for fluorouracil
"No dose of fluorouracil has been proven safe in individuals with absent DPD activity" explicitly states no dose has been proven safe in DPD-null individuals, and multiple fatal outcomes have been documented in these genotypes. Your oncology team must choose an alternative regimen: oxaliplatin- or irinotecan-based chemotherapy for colorectal cancer, anthracycline/taxane protocols for breast cancer, gemcitabine-based regimens for pancreatic cancer, and so on. Uridine triacetate¹¹¹¹ Uridine triacetate
Vistogard — an FDA-approved pyrimidine-analog antidote that bypasses DPD by flooding the system with competing uridine nucleotides is the FDA-approved emergency antidote for life-threatening fluoropyrimidine overdose and must be given within 96 hours of exposure; its existence does not justify exposing known DPD-deficient patients to these drugs in the first place.

Testing DPYD before starting fluoropyrimidine therapy is now mandatory in much of Europe, standard of care in the UK NHS, and cost-effective by every published analysis¹²¹² cost-effective by every published analysis
Preventing one case of severe toxicity saves $155,000-180,000 in hospital and rescue costs, versus ~$160-250 for targeted DPYD panel genotyping. Most commercial DPYD panels test the four CPIC priority variants together — *2A, *13, c.2846A>T, and HapB3 — so a result for one almost always comes with results for the others. If your oncologist has not ordered DPYD testing before prescribing a fluoropyrimidine, request it explicitly and wait for the result before starting treatment.

Interactions

DPYD*13 is one of four clinically actionable DPYD variants that together define DPD metabolizer status in the CPIC activity-score system¹³¹³ CPIC activity-score system
Activity score 2.0 = normal metaboliser; 1.0-1.5 = intermediate metaboliser (heterozygous for a no-function or decreased-function allele); 0-0.5 = poor metaboliser (homozygous or compound heterozygous for actionable variants). 13 and *2A are **no-function* alleles (activity contribution: 0), whereas c.2846A>T and HapB3 are decreased-function alleles (activity contribution: 0.5). Compound heterozygotes — carrying *13 alongside *2A, c.2846A>T, or HapB3 — drop to activity scores of 0-0.5 and are typically treated as poor metabolizers requiring fluoropyrimidine avoidance rather than dose reduction. These combinations are extraordinarily rare but have been documented in case series, with consistently severe outcomes under standard dosing.

Because the four-variant DPYD panel only captures roughly 20-30% of patients who ultimately develop severe fluoropyrimidine toxicity¹⁴¹⁴ roughly 20-30% of patients who ultimately develop severe fluoropyrimidine toxicity
The remaining 70-80% of severe toxicity cases are driven by rare DPYD variants not on the panel, variants in other pyrimidine-pathway genes (TYMS, MTHFR), drug interactions, and non-genetic factors, a normal DPYD*13 result does not eliminate the need for careful clinical monitoring during fluoropyrimidine chemotherapy. Conversely, a *13 carrier result is enormously valuable precisely because it identifies patients for whom the toxicity risk would otherwise be missed. Some academic centres now also measure dihydrouracil/uracil ratio in plasma (a direct biomarker of DPD activity) as a complement to genotyping.

First-degree relatives of *13 carriers have a 50% prior probability of carrying the variant themselves and should be offered DPYD panel testing if they ever face fluoropyrimidine-based cancer treatment. Because *13 is so rare, family members are often the only other documented carriers in a given clinical setting.